Bacterial surface display of endoglin by antigen 43 induces antitumor effectiveness via bypassing immunotolerance and inhibition of angiogenesis

Various angiogenesis‐related self‐molecules have been considered to be therapeutic targets. However, the direct use of self‐molecules as vaccines is not recommended because of the inherent ability of the host to develop immune tolerance. Antigen 43 (Ag43) is a surface protein found in E. coli and co...

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Bibliographic Details
Published in:International journal of cancer 2014-04, Vol.134 (8), p.1981-1990
Main Authors: Huang, Feng‐Ying, Li, Ling, Liu, Quan, Li, Yue‐Nan, Bai, Rui‐Zhen, Huang, Yong‐Hao, Zhao, Huan‐Ge, Guo, Jun‐Li, Zhou, Song‐Lin, Wang, Hua, Lin, Ying‐Ying, Tan, Guang‐Hong
Format: Article
Language:English
Subjects:
Adhesins, Escherichia coli - genetics
Adhesins, Escherichia coli - immunology
Angiogenesis
Animals
antigen 43 surface display system (Ag43 system)
Antigens
Antigens, Bacterial - genetics
Antigens, Bacterial - immunology
Antigens, Surface - genetics
Antigens, Surface - immunology
Bacteria
Biological and medical sciences
Cancer
Cancer therapies
Cancer Vaccines - immunology
Carcinoma, Lewis Lung - immunology
Carcinoma, Lewis Lung - therapy
Endoglin
Epitopes, T-Lymphocyte
Escherichia coli
Escherichia coli - genetics
Escherichia coli - metabolism
immune tolerance
Immune Tolerance - immunology
Intracellular Signaling Peptides and Proteins - genetics
Intracellular Signaling Peptides and Proteins - immunology
Medical research
Medical sciences
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Neovascularization, Pathologic - immunology
Neovascularization, Pathologic - therapy
Recombinant Fusion Proteins - genetics
Recombinant Fusion Proteins - immunology
recombinant vaccine
Tumors
Vaccines
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Summary:Various angiogenesis‐related self‐molecules have been considered to be therapeutic targets. However, the direct use of self‐molecules as vaccines is not recommended because of the inherent ability of the host to develop immune tolerance. Antigen 43 (Ag43) is a surface protein found in E. coli and contains an α and a β subunits, which contains multiple T epitopes in α subunit. Here we construct a novel Ag43 surface display system (Ag43 system) to express Ag43 chimeric proteins to disrupt immune tolerance against self‐molecules. The Ag43 system was constructed from an Escherichia coli strain Tan109, derived from JM109, in which the Ag43 gene was deleted and a recombinant plasmid (pETAg43′) expressing a partial Ag43 gene was introduced. The extracellular domain of angiogenesis‐related endoglin gene was then subcloned into plasmid pETAg43′, resulting in a recombinant plasmid pETAg43′/ENDe which was then used to transform Tan109 for protein expression. We found that Ag43 and endoglin chimeric protein (Ag43′/ENDe) was expressed on the bacterial surface. The chimeric protein could be separated from the bacterial surface by heating to 60°C and yet retain activity. We used Ag43′/ENDe as a protein vaccine and found that it could disrupt immune tolerance against endoglin by inducing significant antitumor activities and inhibit angiogenesis in several tumor models without significant side effects. These data suggest that Ag43′/ENDe chimeric protein is a potential model vaccine for active tumor immunotherapy, and that Ag43 system could be an effective tool for novel vaccine preparation to break immune tolerance to other angiogenesis‐related self‐molecules for cancer therapy. What's new? While various angiogenesis‐related self‐molecules like endoglin have been recognized as potential targets for tumor therapy, the direct use of self‐molecules as vaccines is hampered by the inherent ability of the host to develop immune tolerance. Here, the authors constructed a novel Ag43 bacterial‐surface‐display system to express an antigen 43 and endoglin chimeric protein (Ag43′/ENDe) able to disrupt immune tolerance. The results show that Ag43′/ENDe could be easily expressed and detached from the bacterial surface for direct use as an effective tumor vaccine. The Ag43 system offers an effective tool for novel vaccine preparation to break immune tolerance to other self‐molecules.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.28511